Modified release dosage forms of skeletal muscle relaxants

ABSTRACT

A unit dosage form, such as a capsule or the like, for delivering a skeletal muscle relaxant, such as cyclobenzaprine hydrochloride, into the body in an extended or sustained release fashion comprising one or more populations of drug-containing particles (beads, pellets, granules, etc.) is disclosed. At least one bead population exhibits a pre-designed sustained release profile. Such a drug delivery system is designed for once-daily oral administration to maintain an adequate plasma concentration-time profile, thereby providing relief of muscle spasm associated with painful musculoskeletal conditions over a 24 hour period.

TECHNICAL FIELD

A major objective of developing and commercializing controlled releasedosage forms for indications such as cardiovascular diseases, chronicpain, relief of muscle spasm and associated symptoms especially in theelderly is to deliver the drug so as to maintain the drug attherapeutically effective concentrations over an extended period oftime, thereby enhancing patient compliance and therapeutic efficacy,thereby reducing both cost of treatment and side effects.

BACKGROUND OF THE INVENTION

Many therapeutic agents are most effective when made available at aconstant rate at or near the absorption site. The absorption oftherapeutic agents thus made available generally results in desiredplasma concentrations leading to maximum efficacy and minimum toxic sideeffects. Much effort has been devoted to developing matrix tablet basedand multi-particulate capsule based drug delivery systems for oralapplications.

U.S. Pat. No. 4,839,177 to Colombo, et al, assigned to Jagotec A G,refers broadly to controlled release of active substances includingmedicaments and any type of substance which is to be released at acontrolled rate into an aqueous fluid. The patent is directed to asystem for the controlled-rate release of active substances consistingof a deposit core comprising an active substance and at least one of (a)a polymeric material having a high degree of swelling on contact withwater and a gellable polymeric material or (b) a single polymericmaterial having both swelling and gelling properties, and a supportplatform applied to the deposit core wherein the support platformconsists of a water insoluble polymeric material.

U.S. Pat. No. 4,851,228 and U.S. Pat. No. 4,968,507, both to Zentner etal., assigned to Merck & Company, refer to a multi-particulate osmoticpump for the controlled release of a pharmaceutically active agent, eachosmotic pump element consisting essentially of a core containing anactive agent and a rate controlling water insoluble wall comprising asemi-permeable polymer and at least one pH insensitive pore formingadditive dispersed throughout the wall. U.S. Pat. No. 4,590,062 to Jangassigned to Tech Trade Corporation and U.S. Pat. No. 4,882,167 to Jang,are directed to a compressed product containing an active produced bydry blending with a matrix combination of a hydrophobic polymer (e.g.ethylcellulose) and a wax, fatty acid, neutral lipid or combinationthereof.

U.S. Pat. No. 4,996,047 to Kelleher, assigned to Richardson-Vicks, isdirected to an oral pharmaceutical composition in unit dosage form ofion-exchange resin particles having a pharmacologically active drugbound thereto wherein the drug-resin complex particles have been coatedwith a water-impermeable diffusion barrier to provide controlled releaseof the active drug. U.S. Pat. No. 5,120,548 to McClelland et al.,assigned to Merck & Company, is directed to a controlled release drugdelivery device comprising a composition of a polymer which swells uponexposure to an aqueous environment, a plurality of controlled releaseswelling modulators, at least one active agent and either a waterinsoluble polymer coating surrounding the composition or a microporouswall surrounding the composition. U.S. Pat. No. 5,350,584 to McClellandet al., assigned to Merck & Company, relates to a process for theproduction of microcrystalline cellulose-free multiparticulatescomprising a medicament and a charged resin. The resulting spheronizedbeads can be used in certain controlled release dosage forms.

U.S. Pat. No. 5,366,738 to Rork et al., assigned to Merck & Company, isdirected to a drug delivery device for controlled release of an activeagent. The drug delivery device includes a compressed core with anactive agent and a polymer which forms gelatinous microscopic particlesupon hydration and a water insoluble, water impermeable polymericcoating comprising a polymer and plasticizer which surrounds and adheresto the core.

U.S. Pat. No. 5,582,838 to Rork et al., assigned to Merck & Company, isrelated to a drug delivery device for the controlled release of abeneficial agent. The drug delivery device includes a compressed corehaving at least two layers: at least one layer is a mixture of abeneficial agent and a polymer which forms microscopic polymer gel beadsupon hydration and at least one outer layer comprises a polymer whichforms microscopic polymer gel beads upon hydration. A water insoluble,water impermeable coating is applied to the core and the coating hasapertures exposing between about 5-75% of the core surface.

U.S. Pat. No. 5,874,418 to Stella et al., assigned to Cydex, is directedto a pharmaceutical composition comprising a carrier and a mixture of asulfoalkyl ether-cyclodextrin and a therapeutic agent wherein a majorportion of the therapeutic agent is not complexed to the sulfoalkylether-cyclodextrin derivative. Delayed, sustained or controlled releaseformulations are also described wherein the pharmaceutical core iscoated with a film coating comprising a file forming agent and a poreforming agent. U.S. Pat. No. 5,882,682 to Rork et al., assigned to Merck& Company, is directed to a drug delivery process including the steps ofpreparing a uniform mixture of a polymer which forms gelatinousmicroscopic particles upon hydration, the beneficial agent and otherexcipients used in the preparation of the core; compressing the mixtureinto cores; coating the entire core with a water insoluble, waterimpermeable polymeric coating including a polymer and a plasticizer; andforming apertures through the coating.

U.S. Pat. No. 5,952,451 to Zhao, assigned to Guilford Pharmaceuticals isdirected to a process for preparing high molecular weightpolyphosphoester) compositions comprising a biologically activesubstance and a poly(phosphoester) and the high molecular weightcompositions produced thereby. The polymers so produced are useful inprolonged released drug delivery systems. U.S. Pat. No. 6,004,582 toFaour et al., assigned to Laboratorios Phoenix U.S.A., is directed to amulti-layered osmotic device comprising a compressed core including afirst active agent and an osmotic agent, a semi-permeable membranesurrounding the core and having a preformed passageway therein whereinthe membrane is permeable to a fluid in the environment of use andsubstantially impermeable to the first active agent. The semi-permeablemembrane preferably consists essentially of cellulose acetate andpoly(ethylene glycol). The external coat can includespoly(vinylpyrrolidone) and poly (ethylene glycol) and can furtherincludes materials such as HPMC, ethylcellulose, hydroxylethylcellulose,CMC, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer,ethyl acrylate-methyl methacrylate copolymer, and combinations thereof.

WO 99/18937 to Kleinbart et al., (Merck & Company), is directed to acomposition comprising a pharmaceutically effective amount ofcyclobenzaprine and calcium phosphate dibasic hydrous, wherein thetablet releases most of the active component within an hour. WO 99/30671to Ron, is directed to an oral delivery vehicle including an aspectedparticle comprising a pharmaceutically active component and excipientswherein the vehicle is formulated to provide controlled delivery of thepharmaceutically active component. The vehicle may further contain acoating to provide sustained drug delivery to the particle. WO 98/53802to Faour et al., Laboratorios Phoenix USA), is directed to amulti-layered osmotic device that is capable of delivering a firstactive agent in an outer lamina to one environment of use and a secondactive agent in the core to another environment of use. An erodiblepolymer coat between an internal semipermeable membrane and a secondactive agent-containing external coat comprisespoly(vinylpyrrolidone)-vinyl acetate) copolymer. The active agent in thecore is delivered through a pore containing an erodible plug.

WO 98/18610 to Van Lengerich, is directed to particles containing anactive agent, which provide controlled release of the active ingredientwithout substantial destruction of the matrix material. A release-ratecontrolling component is incorporated in a matrix to control therate-release of the encapsulant from the particles. A hydrophobiccomponent or a high water binding capacity component may be used forextending the release time. Release properties may also be controlled byprecoating the encapsulant and/or coating the particles with afilm-forming component. WO 98/06439 to Oedemoed, (Osteotech), isdirected to a composition comprising a biologically active agentencapsulated in a matrix comprising a polyether ester copolymer, such aspolyethylene glycol terephthalate/polybutylene-terephthalate copolymer.The polyether ester copolymer protects the active agent from degradationand thereby facilitates the drug delivery.

Cyclobenzaprine hydrochloride, a skeletal muscle relaxant, is acentrally acting drug which reduces or abolishes excessive tonic muscleactivity in hypertonic as opposed to hyperphasic disorders. Flexeril IR(immediate release) tablets containing 10 mg of cyclobenzaprine HCl areadministered three times a day to relieve skeletal muscle spasm of localorigin without interfering with muscle function. The oral administrationthrice daily is an issue of patient compliance, especially with theelderly. Hence, there is a need for modified release skeletal musclerelaxant suitable for a single administration. More particularly, thereis a need for modified release (MR) cyclobenzaprine hydrochloridecapsules, 15 and 30 mg, which would substantially minimize intersubjectvariability and improve the quality of life, especially in the elderlypopulation.

SUMMARY OF THE INVENTION

The present invention provides a modified release, multi-particulatedosage form of a skeletal muscle relaxant comprising one or more beadpopulations which provides an extended release profile of the activeunder in vitro conditions closely mimicking the profile simulated frompharmaco-kinetic modeling. One of the bead populations is an ER(extended release) Bead population typically comprising a coating of awater insoluble polymer alone, or in combination with a water solublepolymer, applied onto active containing cores. The active core of thedosage form of the present invention may comprise an inert particle suchas a sugar sphere, or an acidic or alkaline buffer crystal, which iscoated with a skeletal muscle relaxant such as cyclobenzaprinehydrochloride-containing film-forming formulation, preferably awater-soluble film forming composition. The first coating formulationmay contain, in addition to the active, a binder such as hydroxypropylcellulose. The drug layered beads may be coated with a protective sealcoating of OPADRY® Clear to produce IR Beads. Alternatively, the coreparticle may be formed by granulating and dry milling and/or byextrusion and spheronization of a pharmaceutical composition containingthe active. The amount of drug in the core will depend on the doserequired and typically varies from about 5 to about 60% by weight.

ER Beads can be produced by applying a functional membrane comprising awater insoluble polymer alone or in combination with a water solublepolymer onto IR Beads. The capsule formulation for once a day, oraladministration of a skeletal muscle relaxant prepared in accordance withthe present invention comprises ER Beads containing the active substanceand optionally IR Beads. IR (immediate release) Beads allow immediaterelease of the active while ER Beads allow an extended release profileof the active over several hours. Upon oral administration, such acapsule formulation provides for therapeutically effective plasmaprofiles over an extended period of time, thereby resulting in improvedpatient compliance.

In accordance with one embodiment of the invention a pharmaceuticaldosage form of a skeletal muscle relaxant is provided. The dosage formincludes one or more bead populations and provides a modified releaseprofile. At least one of the bead populations includes extended release(ER) beads wherein the ER beads include a core particle (IR (immediaterelease) bead) containing a skeletal muscle relaxant and an ER (extendedrelease) coating comprising a water insoluble polymer surrounding thecore. The dosage form, in accordance with certain embodiments, whendissolution tested using United States Pharmacopoeia Apparatus 2(paddles @ 50 rpm) in 900 mL of 0.1N HCl (or a suitable dissolutionmedium) at 37° C. exhibits a drug release profile substantiallycorresponding to the following pattern:

-   -   after 2 hours, no more than about 40% of the total active is        released;    -   after 4 hours, from about 40-65% of the total active is        released;    -   after 8 hours, from about 60-85% of the total active is        released; and    -   after 12 hours, from about 75-85% of the total active is        released.

The dosage form thereby provides a therapeutically effective plasmaconcentration over an extended period of time, typically over a periodof 24 hours to treat muscle spasm associated with painfulmusculoskeletal conditions in humans.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in further detail with reference to theaccompanying Figures wherein:

FIG. 1 shows the proposed target release profile for cyclobenzaprinehydrochloride MR (modified release) capsules, 15 and 30 mg.

FIG. 2 shows the simulated Day 1 plasma level following dosing of 1×10mg Flexeril® given 3 times a day and 1×30 mg cyclobenzaprine HCl MRcapsule given once-daily.

FIG. 3 shows the drug release profiles for cyclobenzaprine HCl ER(extended release) beads of Example 2.

FIG. 4 compares the drug release profiles as a function of membranecoating of Example 3.

FIG. 5 shows the drug release profiles for cyclobenzaprine HCl ER beadsof Example 3 stored in induction sealed HDPE bottles on acceleratedstability.

FIG. 6 shows the drug release profiles for 30 mg cyclobenzaprine HCl MRcapsules of Example 4.

FIG. 7 shows the plasma levels for cyclobenzaprine HCl MR capsules, 15and 30 mg of Example 5.

DETAILED DESCRIPTION OF THE INVENTION

All documents cited are, in relevant part, incorporated herein byreference; the citation of any document is not to be construed as anadmission that it is prior art with respect to the present invention.

The active core of the dosage form of the present invention may becomprised of an inert particle or an acidic or alkaline buffer crystal,which is coated with a drug-containing film-forming formulation andpreferably a water-soluble film forming composition to form awater-soluble/dispersible particle. Alternatively, the active may beprepared by granulating and milling and/or by extrusion andspheronization of a polymer composition containing the drug substance.The amount of drug in the core will depend on the dose that is required,and typically varies from about 5 to 60 weight %. Generally, thepolymeric coating on the active core will be from about 4 to 20% basedon the weight of the coated particle, depending on the type of releaseprofile required and/or the polymers and coating solvents chosen. Thoseskilled in the art will be able to select an appropriate amount of drugfor coating onto or incorporating into the core to achieve the desireddosage. In one embodiment, the inactive core may be a sugar sphere or abuffer crystal or an encapsulated buffer crystal such as calciumcarbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. whichalters the microenvironment of the drug to facilitate its release.

The drug-containing particle may be coated with an extended release (ER)coating comprising a water insoluble polymer or a combination of a waterinsoluble polymer and a water soluble polymer to provide ER beads. Inaccordance with certain embodiments, the water insoluble polymer and thewater soluble polymer may be present at a weight ratio of from 100/0 to65/35, more particularly from about 95/5 to 70/30, and still moreparticularly at a ratio of from about 85/15 to 75/25. The extendedrelease coating is applied in an amount necessary to provide the desiredrelease profile. The extended release coating typically comprises fromabout 1% to 15%, more particularly from about 7% to 12%, by weight ofthe coated beads.

The present invention also provides a method of making a modifiedrelease dosage form including a mixture of two bead populations. Inaccordance with one embodiment, the method includes the steps of:

-   -   1. preparing a drug-containing core by coating an inert particle        such as a non-pareil seed, an acidic buffer crystal or an        alkaline buffer crystal with a drug and a polymeric binder or by        granulation and milling or by extrusion/spheronization to form        an immediate release (IR) bead;    -   2. coating the IR bead with a plasticized water-insoluble        polymer alone such as ethylcellulose or in combination with a        water soluble polymer such as hydroxypropylmethylcellulose to        form an Extended Release (ER) bead;    -   3. filling into hard gelatin capsules ER Beads alone or in        combination with IR Beads at a proper ratio to produce MR        (modified release) capsules providing the desired release        profile.

IR beads when tested in accordance with the following procedure releaseat least about 70%, more specifically at least about 90% of the activewithin 30 minutes.

Dissolution Procedure:

Dissolution Apparatus: USP Apparatus 2 (Paddles at 50 rpm), dissolutionmedium: 900 mL 0.1N HCl (or a suitable dissolution medium) at 37° C. andDrug Release determination by HPLC).

An aqueous or a pharmaceutically acceptable solvent medium may be usedfor preparing drug-containing core particles. The type of film formingbinder that is used to bind the drug to the inert sugar sphere is notcritical but usually water soluble, alcohol soluble or acetone/watersoluble binders are used. Binders such as polyvinylpyrrolidone (PVP),polyethylene oxide, hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose (HPC), polysaccharides such as dextran, cornstarch may be used at concentrations from about 0.5 to 5 weight %,although other concentrations may be useful. The drug substance may bepresent in this coating formulation in the solution form or may bedispersed at a solid content up to about 35 weight % depending on theviscosity of the coating formulation.

In accordance with certain embodiments, the drug substance, optionally abinder such as PVP, a dissolution rate controlling polymer (if used),and optionally other pharmaceutically acceptable excipients are blendedtogether in a planetary mixer or a high shear granulator such as Fielderand granulated by adding/spraying a granulating fluid such as water oralcohol. The wet mass can be extruded and spheronized to producespherical particles (beads) using an extruder/marumerizer. In theseembodiments, the drug load could be as high as 90% by weight based onthe total weight of the extruded/spheronized core.

Representative muscle relaxants include cyclobenzaprine, dantrolenesodium, methocarbamol, metaxalone, carisoprodol, diazepam andpharmaceutically acceptable salts or derivatives thereof.Cyclobenzaprine hydrochloride is a particularly useful muscle relaxant.As used herein, the useful muscle relaxants include the base,pharmaceutically acceptable salts thereof such as hydrochloride,stereoisomers thereof and mixtures thereof.

Representative examples of water insoluble polymers useful in the ERcoating include ethylcellulose powder or an aqueous dispersion (such asAQUACOAT® ECD-30), cellulose acetate, polyvinyl acetate (KollicoatSR#30D from BASF), neutral copolymers based on ethyl acrylate andmethylmethacrylate, copolymers of acrylic and methacrylic acid esterswith quaternary ammonium groups such as Eudragit NE, RS and RS30D, RL orRL30D and the like. Representative examples of water soluble polymersuseful herein include low molecular weight hydroxypropyl methylcellulose(HPMC), methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone,polyethylene glycol (PEG of molecular weight >3000) and mixturesthereof. The extended release coating will typically be applied at athickness ranging from about 1 weight % up to 15 weight % depending onthe solubility of the active in water and the solvent or latexsuspension based coating formulation used.

The coating compositions used in forming the membranes are usuallyplasticized. Representative examples of plasticizers that may be used toplasticize the membranes include triacetin, tributyl citrate, triethylcitrate, acetyl tri-n-butyl citrate diethyl phthalate, polyethyleneglycol, polypropylene glycol, castor oil, dibutyl sebacate, acetylatedmonoglycerides and the like or mixtures thereof. The plasticizer maycomprise about 3 to 30 wt. % and more typically about 10 to 25 wt. %based on the polymer. The type of plasticizer and its content depends onthe polymer or polymers, nature of the coating system (e.g., aqueous orsolvent based, solution or dispersion based and the total solids).

In general, it is desirable to prime the surface of the particle beforeapplying an extended release membrane coating or to separate thedifferent membrane layers by applying a thin hydroxypropylmethylcellulose (HPMC) (OPADRY® Clear) film. While HPMC is typicallyused, other primers such as hydroxypropylcellulose (HPC) can also beused.

The membrane coatings can be applied to the core using any of thecoating techniques commonly used in the pharmaceutical industry, butfluid bed coating is particularly useful.

The present invention is applied to multi-dose forms, i.e., drugproducts in the form of multi-particulate dosage forms (pellets, beads,granules or mini-tablets) or in other forms suitable for oraladministration. As used herein, these terms are used interchangeably torefer to multi-particulate dosage forms.

The invention also provides a method of making an extended releasedosage form which includes a mixture of two or more bead populations. Inaccordance with one aspect of the present invention, the method includesthe steps of:

-   -   (a) coating an inert particle such as a non-pareil seed, an        acidic buffer crystal or an alkaline buffer crystal with a drug        and polymeric binder to form an active drug particle (IR beads),        which may be present in the unit dosage form to act as a bolus        dose;    -   (b) coating the active drug particle with a solution or        suspension of a water insoluble polymer or a mixture of water        soluble and water insoluble polymers to form an extended release        coated drug particle (ER beads);    -   (c) filling into a hard gelatin capsule ER beads alone and        optionally, in combination with IR beads at a proper ratio        ranging from 95/5 to 70/30 (ER beads/IR beads) to produce a MR        (modified release) capsule exhibiting a target drug release        profile.

The following non-limiting examples illustrate the capsule dosage formsmanufactured in accordance with the invention using cyclobenzaprinehydrochloride as a test case, which exhibit in vitro drug releaseprofiles, similar to that predicted by performing modeling exercises.Such dosage forms when orally administered, would enable maintainingdrug plasma concentrations at therapeutically effective levels overextended periods of time, thereby significantly improving patientcompliance.

EXAMPLE 1

Cyclobenzaprine is well absorbed after oral administration, but there isa large intersubject variation in plasma levels. It is eliminated quiteslowly with a half-life as long as one to three days. The presenttreatment regimen of 10 mg three times daily is an issue of patientcompliance, especially the elderly. Hence, a modified release dosageform (capsule) was designed with a release profile shown in FIG. 1. Todetermine if this is the proper release profile, the pharmacokineticsdata of cyclobenzaprine following a single dose of 10 mg Flexeril®tablets administered 3 times a day was taken from the literature. Apharmacokinetic model was developed from this data using WinNonlin™Version 1.5.

The resulting model parameters are listed below:

Model Parameter Value Volume of Distribution/F 429 L K01 0.2031 hr⁻¹ K100.1004 hr⁻¹ K12 0.0828 hr⁻¹ K21 0.0398 hr⁻¹ Tlag 0 hr Dose 2 × 10 mgTablets

Theoretical plasma levels were simulated using the pharmacokinetic modelgiven above and the target release rate given in FIG. 1. FIG. 2 showsthe simulated plasma levels for day one following dosing of 1×10 mgFlexeril® Tablet given 3 times a day and the proposed CyclobenzaprineHCl MR Capsule, 30 mg given once a day.

EXAMPLE 2

Cyclobenzaprine Hydrochloride (1,200 g) was slowly added to an aqueoussolution of polyvinylpyrrolidone such as Povidone USP (K-29/32, 80 g)and mixed well. # 25-30 mesh sugar spheres (2,640 g) were coated withthe drug solution in a Glatt fluid bed coater, equipped with a 9″ bottomspray Wurster insert to provide IR beads with a coating weight of about9%. The drug containing particles were dried, and a seal coat of OPADRY®Clear (2% w/w) was first applied and dried in the Glatt fluid bed unitas a precautionary measure to drive off excessive surface moisture. Thecomposition and batch quantities of the IR Beads were given in 5 to 10kg. Following the second coating process the IR Beads were passedthrough 14 and 25 mesh screens. Beads remaining on the 14-mesh screenwere discarded as oversized beads and beads passing through the 25-meshscreen were discarded as undersized beads.

The next step in the process was to apply an extended release polymermembrane by spraying AQUACOAT® ECD 30, an aqueous dispersion ofethylcellulose with dibutyl sebacate (76:24), onto the IR Beads for aweight gain of approximately 10%. The same fluid bed equipment was usedto produce ER (extended release) Beads by further coating the AQUACOAT®coated beads with OPADRY® Clear for a weight gain of 2% w/w prior tocuring at 60° C. in a conventional oven for a period of 24 hours. Thebatch size was 5 to 10 kg. The drug release profiles are shown in FIG.3. The figure also shows the drug release profiles from ER Beads storedin induction sealed HDPE bottles at 25° C./60% RH for 6 months.

EXAMPLE 3

Cyclobenzaprine Hydrochloride (2.5 kg) was dissolved in 50/50acetone/purified water. 25-30 mesh Sugar spheres, (7.3 kg) were coatedwith the drug solution in a Glatt fluid bed coater, equipped with a 9″bottom spray Wurster insert. The drug containing particles were dried,and a seal coat of OPADRY® Clear (2% w/w) was first applied and dried inthe Glatt fluid bed unit as a precautionary measure to drive offexcessive surface moisture. 910 g of ethylcellulose (Ethocel PremiumStandard 10 cps) and 90 g of diethyl phthalate were dissolved in 98/02acetone/purified water and applied onto the IR Beads (9 kg) in the GlattGPCG 5 in accordance with the present invention. The release rates ofthe ER Beads will vary depending upon the film weight of the ER coating.One batch of IR Beads was coated for a final weight gain of 7% based onthe weight of coated beads wherein samples of the ER Beads were removedduring the ER coating process to yield beads with increasing coatingweights. Another batch was coated for 10% weight gain and all the coatedbead batches were cured at 60° C. for 4 hours in a conventional oven.FIG. 4 shows the relationship between the ER coating weights and therelease rate of the finished ER coated Beads.

A batch was coated with a 7% ER coating and cured at 60° C. for 4 hours.No changes were noted in the release rates, assay values or impuritylevels after storage in HDPE bottles at 40° C./75% RH for a period of 6months. The release rates for the samples are shown in FIG. 5.

EXAMPLE 4

The drug layering, seal coating, and ER Coating processes were scaled-upto Glatt GPCG 120 equipped with an 18″ bottom spray Wurster insert(batch size: 80 kg for IR Beads and 85 kg for ER Beads). The processparameters of each of the processes were optimized. The drug layeringsolution (9% weight gain), seal coating solution, and the ER coatingsolution (9% weight gain) were sprayed onto the sugar spheres or IRBeads while maintaining the product temperature between narrow limits.Following the seal or ER coating the beads were passed through 14 and 25mesh screens discarding any beads remaining on the 14 mesh screen. TheER Beads were also cured at 60° C. for a period of 4 hours. The ExtendedRelease Beads were then filled into size 4 capsules to produceCyclobenzaprine HCl MR Capsules, 15 and 30 mg. The drug release profilesof 30 mg capsules of one pivotal clinical and three registrationstability batches are presented in FIG. 6

EXAMPLE 5

A Randomized double-blind two-period crossover study to assess thesafety and bioavailability of Cyclobenzaprine HCl Modified-release (CMR)15 mg and 30 mg in healthy male and female volunteers (N=14 or 15) wasperformed. Each subject received one 15 mg or 30 mg capsule of CMR inthe morning, separated by a 14-day washout period between doses. Theresults are presented in Table I and FIG. 7 wherein AUC₀₋₁₆₈ refers tothe area under the plasma concentration-time curve to the lastmeasurable time point (168 hrs) calculated by the linear trapezoidalrule, AUC_(0-∞) refers to area under the concentration-time curve toinfinity, C_(max) refers to the maximum blood plasma concentration andT_(max) refers to the time to maximum plasma levels of cyclobenzaprine.

TABLE 1 Pharmacokinetic Results: Mean (±SD) pharmacokinetic parametersare presented for subjects in the Safety population in the followingtable CMR 15 mg CMR 30 mg N = 15 N = 14 AUC₀₋₁₆₈ (ng · hr/mL) 318.30 ±114.657 736.60 ± 259.414 AUC_(0-∞) (ng · hr/mL) 354.075 ± 119.8037779.889 ± 277.6349 C_(max) (ng/mL) 8.315 ± 2.1635 19.851 ± 5.8765  Timeto Peak, T_(max) (hr) 8.1 ± 2.94 7.1 ± 1.59 Elimination Half-life,t_(1/2) (hr) 33.401 ± 10.2882 31.977 ± 10.1310

The treatments were significantly different from each other as valuesfor AUCs and C_(max) were higher for CMR 30 mg than those for CMR 15 mg.The bioavailability of CMR 30 mg was approximately twice that of CMR 15mg as shown by the AUCs. The adjusted mean ratio of CMR 30 mg to CMR 15mg was greater than about 2 for each of the AUCs and C_(max),specifically the calculated values were 2.42 for AUC₀₋₁₆₈ (p<0.001),2.286 for AUC_(0-∞) (p<0.001), and 2.424 for C_(max)(p<0.001). Overall,both CMR 15 mg and 30 mg were well tolerated during the study.

Accordingly, one aspect of the invention relates to a dosage formcontaining cyclobenzaprine hydrochloride as a skeletal muscle relaxantwherein the pharmaceutical dosage form provides a maximum blood plasmaconcentration (C_(max)) within the range of about 80% to 125% of about20 ng/mL of cyclobenzaprine HCl, an AUC₀₋₁₆₈ within the range of about80% to 125% of about 740 ng·hr/mL and a T_(max) within the range ofabout 80% to 125% of about 7 hours following oral administration of asingle 30 mg cyclobenzaprine HCl MR Capsule.

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made without departingfrom the spirit and scope thereof.

1. A pharmaceutical dosage form of a skeletal muscle relaxant providinga modified release profile comprising a population of extended release(ER) beads, wherein said ER beads comprise an active-containing coreparticle (IR (immediate release) bead) comprising a skeletal musclerelaxant; and an ER (extended release) coating comprising a waterinsoluble polymer membrane surrounding said core, wherein said dosageform when dissolution tested using United States Pharmacopoeia Apparatus2 (paddles @ 50 rpm) in 900 mL of 0.1N HCl at 37° C. exhibits a drugrelease profile substantially corresponding to the following pattern:after 2 hours, no more than about 40% of the total active is released;after 4 hours, from about 40-65% of the total active is released after 8hours, from about 60-85% of the total active is released; and after 12hours, from about 75-85% of the total active is released; therebyproviding therapeutically effective plasma concentration over a periodof 24 hours to treat muscle spasm associated with painfulmusculoskeletal conditions in humans.
 2. A pharmaceutical dosage form asdefined in claim 1, wherein said skeletal muscle relaxant is selectedfrom the group consisting of cyclobenzaprine, dantrolene, methocarbamol,metaxalone, carisoprodol, diazepam, pharmaceutically acceptable salts orderivatives thereof and mixtures thereof.
 3. A pharmaceutical dosageform as defined in claim 2 wherein said skeletal muscle relaxant iscyclobenzaprine hydrochloride and said pharmaceutical dosage formprovides a maximum blood plasma concentration (C_(max)) within the rangeof about 80% to 125% of about 20 ng/mL of cyclobenzaprine HCl and anAUC₀₋₁₆₈ within the range of about 80% to 125% of about 740 ng-hr/mL anda T_(max) within the range of 80% to 125% of about 7 hours followingoral administration of a single 30 mg cyclobenzaprine HCl MR Capsule. 4.A pharmaceutical dosage form as defined in claim 3 wherein the adjustedmean ratio of CMR 30 mg/CMR 15 mg is greater than about 2 for each ofAUC₀₋₁₆₈ (p<0.001), AUC_(0-∞) (p<0.001), and C_(max) (p<0.001).
 5. Apharmaceutical dosage form as defined in claim 1 further comprising animmediate release (IR) bead population, wherein said IR beads whentested in a USP Type 2 Apparatus at 50 rpm in 900 ml 0.1 N HCl at 37° C.release at least about 70% of the active within 30 minutes.
 6. Apharmaceutical dosage form as defined in claim 1, wherein said dosageform comprises only one extended release bead population.
 7. Apharmaceutical dosage form as defined in claim 1, wherein said waterinsoluble polymer is selected from the group consisting of ethers andesters of cellulose, pH-insensitive ammonio methacrylic acid copolymers,and mixtures thereof.
 8. A pharmaceutical dosage form as defined inclaim 7, wherein said extended release coating further comprises aplasticizer.
 9. A pharmaceutical dosage form as defined in claim 8,wherein said plasticizer is selected from the group of triacetin,tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethylphthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol,castor oil, acetylated mono- and di-glycerides and mixtures thereof. 10.A pharmaceutical dosage form as defined in claim 1, wherein said waterinsoluble polymer membrane on the drug cores comprises from about 7% to12% by weight of the coated beads.
 11. A pharmaceutical dosage form asdefined in claim 7, wherein said extended release coating furthercomprises a water soluble polymer selected from the group consisting ofmethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose,polyethylene glycol polyvinylpyrrolidone and mixtures thereof.
 12. Amethod for the preparation of an oral once-daily drug delivery systemcomprising a skeletal muscle relaxant, comprising the steps of: a.preparing an active-containing core to form IR beads; b. coating the IRbeads with an extended release coating comprising a plasticized waterinsoluble polymer to form ER (extended release) beads; and c. fillingcapsules with ER beads and optionally IR Beads at a ratio from about70:30 to 100:0; wherein said dosage form when dissolution tested usingUnited States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of0.1N HCl at 37° C. exhibits a drug release profile substantiallycorresponding to the following pattern: after 2 hours, no more thanabout 40% of the total active is released; after 4 hours, from about40-65% of the total active is released after 8 hours, from about 60-85%of the total active is released; and after 12 hours, from about 75-85%of the total active is released.
 13. The method of claim 12, whereinsaid step of preparing an active-containing core comprises coating aparticle selected from the group consisting of non-pareil seeds, acidicbuffer crystals and alkaline buffer crystals with a water solublefilm-forming composition comprising a muscle relaxant.
 14. The method ofclaim 13 wherein said water soluble film-forming composition furthercomprises a polymeric binder.
 15. The method of claim 12, wherein saidstep of preparing an active-containing core comprises granulating andmilling and/or extruding and spheronizing a polymer compositioncontaining a muscle relaxant.
 16. The method of claim 12, wherein saidextended release coating on the drug cores comprises from about 7% to12% by weight of the coated beads.
 17. The method of claim 12, whereinsaid muscle relaxant is selected from the group consisting ofcyclobenzaprine, dantrolene, methocarbamol, metaxalone, carisoprodol,diazepam, pharmaceutically acceptable salts or derivatives thereof andmixtures thereof.
 18. The method of claim 12, wherein the musclerelaxant comprises cyclobenzaprine hydrochloride.
 19. The method ofclaim 18 wherein said pharmaceutical dosage form provides a maximumblood plasma concentration (C_(max)) within the range of about 80% to125% of about 20 ng/mL of cyclobenzaprine HCl, an AUC₀₋₁₆₈ within therange of about 80% to 125% of about 740 ng·hr/mL and a T_(max) withinthe range of 80% to 125% of about 7 hours following oral administrationof a single 30 mg cyclobenzaprine HCl MR Capsule.
 20. The method ofclaim 12 wherein said extended release coating further comprises aplasticizer selected from the group consisting of triacetin, tributylcitrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethylphthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol,castor oil and acetylated mono- and di-glycerides and mixtures thereof.21. The method of claim 12, wherein said extended release coatingcomprises ethylcellulose plasticized with diethyl phthalate.
 22. Amethod of providing a patient with an oral dosage form, which comprisesadministering to said patient a sufficient amount of a dosage form ofclaim 3 to provide a total dose of 15 or 30 mg of cyclobenzaprinehydrochloride once a day.